U.S. patent number 7,732,561 [Application Number 11/991,282] was granted by the patent office on 2010-06-08 for random copolymers of oxazoline.
This patent grant is currently assigned to Japan Science and Technology Agency. Invention is credited to Kazunori Kataoka, Joon-Sik Park, Yuichi Yamasaki.
United States Patent |
7,732,561 |
Kataoka , et al. |
June 8, 2010 |
Random copolymers of oxazoline
Abstract
The invention provides approximately monodispersible random
copolymers obtained from monomeric mixtures of 2-ethyl-2-oxazoline
with 2-isopropyl-2-oxazoline, production method thereof and
2-isopropyl-2-oxazoline homopolymer obtained by using special
initiator. Such polymers exhibit temperature-responsiveness in an
aqueous solution within a broad temperature range, and are useful
materials in the technical fields of surface chemistry and
biomaterials.
Inventors: |
Kataoka; Kazunori (Tokyo,
JP), Yamasaki; Yuichi (Tokyo, JP), Park;
Joon-Sik (Tokyo, JP) |
Assignee: |
Japan Science and Technology
Agency (Saitama, JP)
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Family
ID: |
37809011 |
Appl.
No.: |
11/991,282 |
Filed: |
August 30, 2006 |
PCT
Filed: |
August 30, 2006 |
PCT No.: |
PCT/JP2006/317587 |
371(c)(1),(2),(4) Date: |
February 29, 2008 |
PCT
Pub. No.: |
WO2007/026932 |
PCT
Pub. Date: |
March 08, 2007 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20090156782 A1 |
Jun 18, 2009 |
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Foreign Application Priority Data
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Sep 1, 2005 [JP] |
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2005-253977 |
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Current U.S.
Class: |
528/392;
528/423 |
Current CPC
Class: |
C08G
73/0233 (20130101) |
Current International
Class: |
C08G
67/02 (20060101) |
Field of
Search: |
;528/392 |
Foreign Patent Documents
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2-155929 |
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Jun 1990 |
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JP |
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2-182724 |
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Jul 1990 |
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JP |
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4-41600 |
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Feb 1992 |
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JP |
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4-128207 |
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Apr 1992 |
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JP |
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4-128208 |
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Apr 1992 |
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JP |
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05-117390 |
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May 1993 |
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JP |
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05-310929 |
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Nov 1993 |
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JP |
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8-286313 |
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Nov 1996 |
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JP |
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Other References
Uyama, H. et al. A Novel Thermo-Sensitive Polymer. Chem Lett.,
(1992), pp. 1643-1646. cited by other .
Kataoka, K. et al. Block copolymer micelles as vehicles for drug
delivery, J. Controlled Release, vol. 24, (1993), pp. 119-132.
cited by other .
Woodle, M. et al. New Amphipatic Polymer-Lipid Conjugates Forming
Long-Circulating Reticuloendothelial System-Evading Liposomes,
Bioconjugate Chem., vol. 5, No. 6, (1994), pp. 493-496. cited by
other .
Park, J. et al. Versatile Synthesis of End-Functionalized
Thermosensitive Poly(2-isoprophl-2-oxazolines), Macromolecules,
vol. 37, (2004), pp. 6786-6792. cited by other.
|
Primary Examiner: Gulakowski; Randy
Assistant Examiner: Fang; Shane
Attorney, Agent or Firm: Wenderoth, Lind & Ponack,
L.L.P.
Claims
The invention claimed is:
1. A production method of a homopolymer represented by the
following formula: ##STR00008## wherein R.sup.3 stands for hydrogen
or C.sub.1-5 alkyl, m stands for an integer of 1-20, and n stands
for an integer of 5-10,000, which comprises a step of ring-opening
polymerizing with 2-isopropyl-2-oxazoline in an inert solvent at
30.degree. C.-50.degree. C. in the presence of a cationic
polymerization initiator, a step of reacting the resultant
homopolymer with a nucleophilic agent, and, where necessary, a step
of isolating the formed homopolymer.
2. The production method according to claim 1, in which the
cationic polymerization initiator is a substituted or
unsubstituted, straight chain or branched C.sub.1-20 alkyl
tosylate.
3. The production method according to claim 2, in which the
substituent on the substituted straight chain or branched
C.sub.1-20 alkyl is represented by a formula, ##STR00009## or a
formula, R.sup.3C.ident.C--, wherein R.sup.1 and R.sup.2 either
stand for C.sub.1-10 alkoxy, aryloxy or aryl-C.sub.1-3 alkyloxy,
independently of each other, or R.sup.1 and R.sup.2 together stand
for optionally C.sub.1-5 alkyl-substituted ethylenedioxy
(--O--CH(R')--CH.sub.2--O--, R' being hydrogen or C.sub.1-5 alkyl)
or oxy (.dbd.0) group, and R.sup.3 stands for hydrogen or C.sub.1-5
alkyl.
4. A homopolymer represented by the following formula ##STR00010##
in the formula, R.sup.3 stands for hydrogen or C.sub.1-5 alkyl, m
stands for an integer of 1-20, and n stands for an integer of
5-10,000.
Description
TECHNICAL FIELD
This invention relates to random copolymers derived from two kinds
of oxazolines. More specifically, the invention relates to
monodispersible poly(ethyloxazoline-ran-isopropyloxazoline) whose
lower critical solution temperature (LCST) is controlled, and
method for preparation thereof.
BACKGROUND ART
It is becoming clear in these years that poly(oxazoline) (hereafter
may be abbreviated as POx) are useful materials in the art of
surface chemistry and biological materials, because they act as
nonionic surfactant, protein modifier, hydrogel and carrier of
medicines. Cationic ring-opening polymerization of oxazoline under
adequate conditions is known to progress by living polymerization
process to provide poly(N-acrylethyleneimine). A wide variety of
POx can be produced by changing alkyl substituent or terminal group
of starting oxazoline. Those POx's having short chain alkyl (e.g.,
methyl or ethyl group) at 2-position of side chain are
water-soluble. Hydrophilicity of POx, however, decreases with
increase in length of the alkyl substituent, until it becomes
water-insoluble at all temperatures or at a certain fixed
temperature. Of those POx's poly(2-isopropyl-2-oxazoline) (which
hereafter may be abbreviated as PiPrOx) having isopropylcarbonyl
group at 2-position of side chain are of particular interest. These
polymers are soluble in cold water, and their aqueous solutions
have their cloud points in the vicinity of physiological conditions
(cf. Patent Reference 1 or Non-patent Reference 1 identified below.
All References cited in this clause are collectively listed later).
This is a property analogous to that of poly(N-isopropylacrylamide)
which is a typical temperature-responsive polymer having versatile
utilities.
Main merit of PiPrOx which are POx homologs is that they can be
strongly expected to be biocompatible temperature-responsive
polymers and hence are per se very useful in biomedical utilities.
For example, liposomes modified with poly(2-ethyl-2-oxazoline)
exhibit high biocompatibility and long blood circulation time (see
Non-patent Reference 3) comparable to those of ordinary
poly(ethylene glycol) lipopolymer (e.g., see Non-patent Reference
2). Besides, as temperature-responsive PiPrOx which are expected to
open up new field of utility, monodispersible heterotelechelic
PiPrOx having different functional groups at .alpha.-terminal and
.omega.-terminal and the cloud point at about 37.degree. C. have
also been provided (cf. Non-patent Reference 4). (1) Patent
Reference 1: JP Hei 5 (1993)-310929A (2) Non-patent Reference 1:
Uyama, H., et al., Chem. Lett., 1992, 1643 (3) Non-patent Reference
2: Kataoka, K., et al., J. Controlled Release, 1993, 24, 119 (4)
Non-patent Reference 3: Woodle, I. M., et al., Bioconjugate Chem.,
1994, 5, 493 (5) Non-patent Reference 4: Park, J., et al.,
Macromolecules, 2004, 37, 6786
DISCLOSURE OF THE INVENTION
Although PiPrOx which is described in Patent Reference 1 or
Non-patent Reference 1 shows certain temperature-responsive
property, it cannot be necessarily regarded as an assembly of
polymers which exhibit dispersibility close to monodispersibility.
On the other hand, according to Non-patent Reference 4, a polymer
which exhibits degree of dispersion (Mw/Mn) worth being called
monodispersibility, such as not higher than 1.15 and which,
furthermore, shows distinct cloud point slightly variable depending
on the polymer concentration in its aqueous solution is offered by
selecting mild polymerization reaction conditions, although longer
polymerization time is required. However, utility of POx will be
further broadened, if the polymer whose temperature-responsive
property is so controlled that it will show distinct cloud point or
lower critical solution temperature (LCST) at certain temperature
within a still wider range could be provided.
We have discovered that different monomers, 2-isopropyl-2-oxazoline
and 2-ethyl-2-oxazoline, could form polymers showing distinct cloud
point or LCST at certain temperatures over a wide range, without
being substantially affected by their blend ratio, in other words,
without forming respective whole or partial block segments or the
like attributable to the two monomers, even under such mild
polymerization reaction conditions as described in Non-patent
Reference 4. It is surprising that polymers whose LCST is
controlled as above can be provided with use of these polymers,
against the anticipation that the progress rates of living
polymerization process of 2-isopropyl-2-oxazoline and
2-ethyl-2-oxazoline would be considerably different under mild
reaction conditions.
The present invention is completed, based on the above discovery.
Accordingly, the invention provides random copolymers represented
by the following formula (A):
##STR00001## in the formula, In stands for a residue of a cationic
polymerization initiator, NP stands for a residue of a nucleophilic
agent, and m and n are integers of 5-10,000 independently of each
other, m+n being an integer of 10-20,000 and m:n being, in terms of
molar ratio, 1:99-99:1.
As another embodiment of the present invention, a method of
producing the random copolymer is provided, which comprises a) a
step of subjecting a monomeric mixture of 2-ethyl-2-oxazoline with
2-isopropyl-2-oxazoline at a molar ratio of 1:99-99:1 to a
ring-opening polymerization in an inert solvent of 30.degree.
C.-50.degree. C. in the presence of a cationic polymerization
initiator; b) a step of reacting the resulting random copolymer
with a nucleophilic agent, and c) where necessary, a step of
isolating the formed polymer.
DETAILED DESCRIPTION OF THE INVENTION
The term, random copolymer, as used in the "random copolymers
represented by the formula A" signifies the concept commonly
accepted in the concerned art.
The straight chain or branched C.sub.1-20 alkyl which are used for
specifying the random copolymers are alkyl groups having 1 to 20
carbon atoms, examples of which include, although not limited
thereto, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
sec-butyl, hexyl, octyl, dodecyl, octadecyl, eicosyl and
18-methylnonadecanyl. Similarly, C.sub.1-5 alkyl and alkyl moieties
of C.sub.1-20 alkoxy and aryl-C.sub.1-3 alkyl which are used to
specify the random copolymers are those alkyl groups as exemplified
in the above, each containing the respective number of carbon
atoms. "Aryl" in aryloxy means such groups which are formed upon
elimination of one hydrogen atom bound to such aromatic hydrocarbon
ring as phenyl, tolyl, naphthyl and the like.
The residue derived from cationic polymerization initiator, which
specifies In in the formula (A) may be any group, so long as it is
a residue of a polymerization initiator capable of providing random
copolymers meeting the object of the present invention. Although
not in limitative sense, it can be one corresponding to group R
where a great variety of tosylates are expressed by a general
formula: TsOR, and can be an optionally substituted alkyl group in
alkanols or substituted alkanols. It can also be poly(oxazoline)
(or poly(N-acylethyleneimine)). While it is unnecessary to limit
the number of carbon atoms or degree of branching of the alkyl
groups, so long as they have no adverse effect on
temperature-responsive property of
poly(2-ethyl-2-oxazoline-ran-2-isopropyl-2-oxazoline) segments in
the formula (A), consisting of m and n recurring units,
respectively, generally they can be C.sub.1-20 alkyl groups.
Preferred alkyl groups are those belonging to the category of so
called "lower alkyl groups".
Where they are substituted, the substituent can be any organic
group or moiety, so long as it is a substituent not detrimental to
the cationic ring-opening living polymerization of oxazolines
according to the present invention. Examples of the substituent
include halogen atom (preferably fluorine, chlorine or bromine),
lower alkoxy, ethylenically unsaturated group-containing group and
acetylenically unsaturated group-containing group (or alkynyl).
While not limited thereto, preferred substituents are those
represented by the formula:
##STR00002## wherein R.sup.1 and R.sup.2 each independently stands
for C.sub.1-10 alkoxy, aryloxy or aryl-C.sub.1-3 alkyloxy; or
R.sup.1 and R.sup.2 may together stand for optionally C.sub.1-5
alkyl-substituted ethylenedioxy (--O--CH(R')--CH.sub.2--O--, where
R' is hydrogen or C.sub.1-5 alkyl). Another preferred group of
substituents are alkynyl represented by the formula:
R.sup.3C.ident.C-- wherein R.sup.3 stands for hydrogen or C.sub.1-5
alkyl.
Such a substituent can be at a position as remote as possible from
the binding site of the alkyl group to the recurring units, i.e.,
referring to the formula (A), preferably substitutes the hydrogen
atom at the .alpha.-terminal. Such a substituent corresponds to an
acetal residue and can be easily converted to highly functional
formyl or aldehyde group (--CHO) by hydrolysis under mild
conditions, and hence is preferred also for this reason. On the
other hand, alkynyl group is a simple terminal functional group
capable of binding plural compounds with ease and high efficiency,
and is preferred for introduction of target-directive ligand or
application to click chemistry such as of bioconjugates, as it can
selectively form triazole bond without side reaction at the desired
site, once various azide group-containing compounds (e.g., folic
acid, peptide (such as RGD peptide), enzyme, biocompatible high
polymer such as poly(ethylene glycol), polyamino acid and the like)
are synthesized. Recently various chemical modifications on surface
of enzymes or virus or development of dendrimers using click
chemistry are reported, and application of the technology for
developing artificial functional protein also is expected.
The residue derived from the nucleophilic agent, which specifies NP
in the formula (A), can be introduced by direct reaction with a
living polymer which can be a precursor of the random copolymer
represented by the formula (A), or it may be a group or moiety
which can be introduced through further reaction via the once
introduced residue. Although not limited thereto, examples of such
a residue include --OH, --SH, --NH.sub.2, --CN, --COOH,
--OCOC(CH.sub.3) .dbd.CH.sub.2, --OCOCH.dbd.CH.sub.2,
--OCH.sub.2CH.dbd.CH.sub.2 and --OCH.sub.2-Ph-CH.dbd.CH.sub.2.
Therefore, as preferred nucleophilic agent, anionoid reagents which
produce anionoids corresponding to above residues can be named.
In the formula (A), m and n respectively are the numbers of
recurring units derived from 2-ethyl-2-oxazoline and those derived
from 2-isopropyl-2-oxazoline, which constitute the random
copolymer, and stand for an integer of 5-10,000, independently of
each other. From the viewpoint of indicating distinct LCST, m+n is
preferably 10-200, but for general utility of POx, these integers
can be much greater. The ratio between m and n in the random
copolymer can range, as m:n, 1:99-99:1. Whereas for exhibiting the
characteristics of the copolymers more distinctly, m:n is
preferably within the range of 10:90-90:10, in particular,
20:80-80:20.
A molecular assembly formed of the copolymer of the present
invention as specified in the foregoing is preferably
monodispersible, but is not thereby limited.
The molecular assembly formed of the copolymer as referred to in
this invention normally means an assembly of the copolymer
molecules contained in the product resulting from the
copolymerization reaction, and one prepared from the reaction
product by, e.g., specific molecular weight fractionation, is not
intended. Strictly speaking, monodispersibility means that the
degree of dispersion (Mw/Mn) is 1, but in the present invention the
term signifies a property of copolymers whose degree of dispersion
is not more than 1.2, preferably not more than 1.15 and which have
narrow molecular weight distribution and can be substantially
monodispersed. Furthermore, when desired, the invention can provide
copolymers the cloud point of whose 1 wt % aqueous solution is
controlled to a value within a range of about 37.degree.
C.-67.degree. C., or molecular assemblies of such copolymers.
Thus, the copolymers or molecular assemblies formed of the
copolymers that are provided by the present invention not only
possess temperature-responsiveness but also exhibit characteristic
properties such as monodispersibility, and are useful particularly
as medical materials for which qualitative uniformity is required.
Needless to say, they can be also broadly used in the technical
fields of surface chemistry and biomaterials in which known POx in
general have been used.
According to the present invention, furthermore, homopolymers
represented by the following formula can also be provided:
##STR00003##
in which R.sup.3 stands for hydrogen atom or a C.sub.1-5 alkyl; m
stands for an integer of 1-20, preferably 1-3; and n stands for an
integer of 5-10,000, preferably 10-1,000, inter alia, 10-200.
Those copolymers represented by the formula (A) or molecular
assemblies formed of the copolymers can be conveniently produced
through the cationic ring-opening living polymerization which is
provided as another embodiment of the present invention. According
to this production method, a monomeric mixture of
2-ethyl-2-oxazoline and 2-isopropyl-2-oxazoline is dissolved in an
inert solvent containing cationic polymerization initiator, e.g.,
aprotic polar solvent solution such as acetonitrile, nitromethane
or the like, and the polymerization reaction is carried out at
30.degree. C.-50.degree. C. Depending on the desired
temperature-responsiveness of the product copolymer, the molar
ratio of 2-ethyl-2-oxazoline to 2-isopropyl-2-oxazoline in the
monomeric mixture can be selected within a range of 1:99-99:1,
preferably 10:90-90:10, inter alia, 20:80-80:20. According to the
method of the present invention, the polymerization process
advances in living polymerization mode and therefore, when the
reaction is continued long enough to allow the total amount of
these monomers fed for the reaction to react, the numbers of the
recurring units derived from the respective monomers in the
resulting copolymer approximately correspond to the quantitative
ratio of the fed monomers.
The reaction temperature may be lower than 30.degree. C., but at
such low temperatures many hours are required until the fed
monomers completely react, which cannot be necessarily practical
for industrial production. Conversely, at temperatures exceeding
50.degree. C., side reactions tend to take place to give copolymers
of broad molecular weight distribution. It is therefore
recommendable to select reaction temperature of, more preferably,
35.degree. C.-45.degree. C. The monomeric concentration in the
reaction liquid is not critical, so long as the monomers can be
dissolved in the solvent, while it can be 15-50 wt %, preferably
30-40 wt %. The reaction liquid is preferably stirred during the
reaction. The reaction time preferably is such that allows
substantially all the monomers are consumed. Where necessary, the
residual amount of the monomeric component in the reaction liquid
can be traced by a per se known method of analysis. The reaction
time normally is about 200- about 500 hours.
A nucleophilic agent is added to thus obtained reaction liquid to
introduce NP in the formula (A) in situ. Alternatively, OH groups
as NP are introduced into the living copolymer by treating the
copolymer with a nucleophilic agent or anionoid-producing anionoid
reagent such as sodium hydroxide, and where necessary, then
recovered copolymer may be subjected to a further reaction to
convert the OH group to other desired functional group. Thus the
copolymers represented by the formula (A) can be produced. The
recovery and isolation of the copolymers out can be carried out by
the means will known in the art.
The above homopolymers or molecular assemblies formed of the
polymers can be produced under the conditions similar to those for
producing the copolymers, except that the use of the two kinds of
monomers in the copolymer production is changed to the use of
2-isopropyl-2-oxazoline, and, in particular, alkynyl-alkyl tosylate
is used as the cationic polymerization initiator.
BRIEF EXPLANATION OF DRAWINGS
FIG. 1 shows GPC diagrams of three kinds of the random copolymers
(PEtOx.sub.25%iPrOx.sub.75%, PEtOx.sub.50%iPrOx.sub.50%, and
PEtOx.sub.75%iPrOx.sub.25%) having hydroxyl group at
.omega.-terminal, as obtained in Production Examples 1-3 (this
invention). In the figure, A shows PEtOX.sub.25%iPOx.sub.75%after
310 hours of the reaction (polymerization completed); B shows
PEtOx.sub.50%iPrOx.sub.50%after 407 hours of the reaction
(polymerization completed); and C shows
PEtOx.sub.75%iPrOx.sub.25%after 288 hours of the reaction
(polymerization completed).
FIG. 2 shows .sup.1H-NMR (CDCl.sub.3, 400 MHz) spectrum of the
random copolymer PEtOx.sub.25%iPrOx.sub.75%having hydroxyl group at
.omega.-terminal, as obtained in Production Example 1 (this
invention)
FIG. 3 shows .sup.1H-NMR (CDCl.sub.3, 400 MHz) spectrum of the
random copolymer PEtOx.sub.50%iPrOx.sub.50% having hydroxyl group
at .omega.-terminal, as obtained in Production Example 2 (this
invention)
FIG. 4 shows .sup.1H-NMR (CDCl.sub.3, 400 MHz) spectrum of the
random copolymer PEtOx.sub.75%iPrOx.sub.25% having hydroxyl group
at .omega.-terminal, as obtained in Production Example 3 (this
invention)
FIG. 5 shows MALDI-TOF-MS spectra of three kinds of random
copolymers having hydroxyl group at .omega.-terminal, as obtained
in Production Examples 1-3 (this invention). In the same figure, A
shows the spectrum of PEtOx.sub.25%iPrOx.sub.75%, B shows that of
PEtOx.sub.50%iPrOx.sub.50% and C, that of
PEtOx.sub.75%iPrOx.sub.25%.
FIG. 6-A shows measurement of the temperature at which percent
transmission drops (cloud point, Tcp) at the polymer concentration
of 1 wt % (10 mg/mL) and temperature rise rate of 0.5 deg/min. FIG.
6-B shows measurement of changes in the cloud point versus the
ratio of 2-ethyl-2-oxazoline (EtOx) (25%, 50%, and 75%) in the
random copolymers. In the figure, .diamond-solid. (150 mM salt
concurrently present) and .diamond. (no salt) are for iPrOx
homopolymer (PiPrOx.sub.100%) having hydroxyl group at
.omega.-terminal; .circle-solid. (150 mM salt concurrently present)
and .largecircle. (no salt) are for the random copolymer
PEtOx.sub.25%iPrOx.sub.75% having hydroxyl group at
.omega.-terminal; .tangle-solidup. (150 mM salt concurrently
present) and .DELTA. (no salt) are for the random copolymer
PEtOX.sub.50%iPrOx.sub.50% having hydroxyl group at
.omega.-terminal; and .box-solid. (150 mM salt concurrently
present) and .quadrature. (no salt) are for the random copolymer
PEtOx.sub.75%iPrOx.sub.25% having hydroxyl group at
.omega.-terminal.
FIG. 7 shows GPC diagram of the propargyl-PiPrOx-OH as obtained in
Production Example 4 (this invention).
FIG. 8 shows .sup.1H-NMR spectrum (CDCl.sub.3, 400 MHz) of the
propargyl-PiPrOx-OH as obtained in Production Example 4 (this
invention).
FIG. 9 shows MALDI-TOF-MS spectrum of the Propargyl-PiPrOx-OH as
obtained in Production Example 4 (this invention).
BEST MODE FOR PRACTICING THE INVENTION
Hereinafter the invention is more specifically explained, referring
to working Examples.
Referential Production Example 1
Cationic ring-opening polymerization of 2-isopropyl-2-oxazoline
(iPrOx) and synthesis of poly(2-isopropyl-2-oxazoline (PiPrOx)
homopolymer therefrom
##STR00004##
In an atmosphere of dry argon, 0.186 g (1 mmol) of methyl tosylate
as the initiator and 10 g (88.4 mmols) of an iPrOx monomer were
added to 30 mL of acetonitrile solvent, to effect its cationic
ring-opening polymerization (theoretical molecular weight=10,000
and the theoretical degree of polymerization=[iPrOx]/[methyl
tosylate]=88.4). The reaction was carried out for about 506 hours,
at the optimum reaction temperature of 42.degree. C. in a
thermostat, and then the reaction system was cooled to room
temperature. For introducing hydroxyl group at termination terminal
of the polymer, 10 mL of 1M NaOH-methanol mixed solvent was added,
followed by 30 minutes' termination reaction. The reaction mixture
was purified by dialysis against water, and dried under reduced
pressure to provide about 9 g (yield, 90%) of the polymer. The
molecular weight (Mn=9700) of the finally obtained polymer well
coincided with that of the feed, and the molecular weight
distribution of the polymer (Mw/Mn=1.02) was very narrow.
Construction of the polymer was analyzed with .sup.1H-NMR spectrum,
and by terminal analysis using MALDI-TOF-MS spectrum, the polymer
was confirmed to have a structure as shown by the above
formula.
Referential Production Example 2
Cationic ring-opening polymerization of 2-ethyl-2-oxazoline (EtOx)
and synthesis of poly(2-ethyl-2-oxazoline) (PEtOx) homopolymer
therefrom
##STR00005##
In an atmosphere of dry argon, 0.186 g (1 mmol) of methyl tosylate
as the initiator and 8.92 mL (88.4 mmols) of EtOx monomer were
added to 30 mL of acetonitrile solvent to effect its cationic
ring-opening polymerization (theoretical molecular weight=8,800,
the theoretical degree of polymerization=[EtOx]/[methyl
tosylate]=88.4). The reaction was carried out for about 315 hours,
at the optimum reaction temperature of 42.degree. C. in a
thermostat, and then the reaction system was cooled to room
temperature. For introducing hydroxyl group at termination terminal
of the polymer, 10 mL of 1M NaOH-methanol mixed solvent was added,
followed by 30 minutes' termination reaction. The reaction mixture
was purified by dialysis against water, and dried under reduced
pressure to provide about 8.3 g (yield, 95%) of the polymer. The
molecular weight (Mn=8300) of the finally obtained polymer well
coincided with that of the feed, and the molecular weight
distribution of the polymer (Mw/Mn=1.01) was very narrow.
Construction of the polymer was analyzed with .sup.1H-NMR spectrum,
and by terminal analysis using MALDI-TOF-MS spectrum, it was
confirmed that hydroxyl group was quantitatively introduced at the
termination terminal and that a polymer of the above structural
formula was obtained.
Referential Production Example 3
Cationic ring-opening polymerization of 2-isopropyl-2-oxazoline
(iPrOx) initiated by 3,3-diethoxy-1-propyl tosylate (AceOTs) and
synthesis of poly(2-isopropyl-2-oxazoline having .alpha.-acetal and
.omega.-ahydroxyl groups (Acetal-PiPrOx-OH) homopolymer
In an atmosphere of dry argon, 0.3 g (1 mmol) of methyl tosylate as
an initiator and 9.74 g (86 mmols) of iPrOx monomer were added to
30 mL of acetonitrile solvent, to effect its cationic ring-opening
polymerization (theoretical molecular weight=10,000, the
theoretical degree of polymerization=[iPrOx]/[methyl tosylate]=86).
The reaction was carried out for about 240 hours, at the optimum
reaction temperature of 45.degree. C. in a thermostat and then the
reaction system was cooled to room temperature. For introducing
hydroxyl group at termination terminal of the polymer, 20 mL of 1M
NaOH-methanol mixed solvent was added, followed by 30 minutes'
termination reaction. The product was purified by dialysis against
water and dried under reduced pressure. About 8 g (yield, 80%) of
the polymer was recovered. The molecular weight (Mn=9600) of the
finally obtained polymer well coincided with that of the feed, and
the molecular weight distribution of the polymer (Mw/Mn=1.15) was
very narrow. Construction of the polymer was analyzed with
.sup.1H-NMR spectrum, and by terminal analysis using MALDI-TOF-MS
spectrum, it was confirmed that hydroxyl group was quantitatively
introduced at the termination terminal.
Production Examples 1-3 (the present invention)
Cationic ring-opening polymerization of monomeric mixture of iPrOx
and EtOx and synthesis of three kinds of random copolymers
(PiPrOx-ran-PEtOx)
##STR00006##
iPrOx (monomer) and EtOx (hydrophilic comonomer) were mixed at
various ratios (EtOx.sub.A:iPrOx.sub.A=25%:75%,
EtOx.sub.B:iPrOx.sub.B=50%:50%, EtOx.sub.C:iPrOx.sub.C=75%:25%),
and each of the mixtures was subjected to precision random ionic
copolymerization. In dry argon atmosphere, 0.15 mL (1 mmol) of
methyl tosylate as the initiator and each of the monomeric mixtures
(EtOx.sub.A+iPrOx.sub.A=2.19 g+7.502 g=9.692 g,
EtOx.sub.B+iPrOx.sub.B=4.3815 g+5 g=9.3815 g,
EtOx.sub.C+iPrOx.sub.C=6.57 g+2.5 g=9.07 g) were added to 30 mL of
acetonitrile solvent to carry out cationic ring-opening
polymerization (the theoretical degree of
polymerization.sub.m+n=[monomeric mixture].sub.A, B, C/[methyl
tosylate]=88.4). At the optimum reaction temperature of 42.degree.
C. in a thermostat, the reaction systems were reacted for,
respectively, 310 hours (A), 407 hours (B) and 288 hours (C) and
thereafter cooled to room temperature. For introducing hydroxyl
group at each polymer's termination terminal, 10 mL of 1M
NaOH-methanol mixed solution was added to cause 30 minutes'
termination reaction. The reaction products were purified by
dialysis against water and dried under reduced pressure. Whereupon
the polymers (PEtOx.sub.AiPrOx.sub.A: about 8.4 g (yield, 87%),
PEtOx.sub.BiPrOx.sub.B: about 8.5 g (yield, 91%),
PEtOx.sub.ciPrOx.sub.C: about 7.7 g (yield, 85%) were recovered. It
was confirmed on the GPC diagrams (FIG. 1) that the molecular
weight of the polymers versus polymerization time changed with
time. The degree of polymerization (m+n) (PEtOx.sub.AiPrOx.sub.A:
81.8, PEtOx.sub.BiPrOx.sub.B: 88, PEtOx.sub.ciPrOx.sub.c: 85.9) of
the ultimately obtained polymers were coincided with the fed
amounts, and the polymers' molecular weight distribution values
(Mw/Mn) (PEtOx.sub.AiPrOx.sub.A: 1.00, PEtOx.sub.BiPrOx.sub.B:
1.01, PEtOx.sub.CiPrOx.sub.C: 1.01) were invariably very narrow.
For the structural analysis of the polymers, their .sup.1H-NMR
spectra were used (cf. FIGS. 2, 3 and 4). Also by the terminal
analyses with MALDI-TOF-MS spectra, it was confirmed that each of
the polymers was copolymerized at random (cf. FIG. 5).
Production Example 4 (the present invention)
Synthesis of poly(2-propargylisopropyl-2-oxazoline
(propargyl-PiPrOx-OH) homopolymer having propargyl group at the
initiation terminal and hydroxyl group at the termination
terminal
##STR00007##
In an atmosphere of dry argon, 0.0486 g (0.231 mmol) of propargyl
tosylate (initiator) and 1.25 g (11 mmols) of
2-isopropyl-2-oxazoline (monomer) were added to 5 mL of
acetonitrile solvent and the cationic ring-opening polymerization
was carried out (theoretical molecular weight=5400, the theoretical
degree of polymerization=[iPrOx]/[methyl tosylate]=47.6). The
reaction was continued for about 227 hours at the optimum reaction
temperature of 42.degree. C. in a thermostat, and then the reaction
system was cooled to room temperature. For introducing hydroxyl
group at the termination terminal of the polymer, 5 mL of 1M
NaOH-methanol mixed solvent was added, followed by 30 minutes'
termination reaction. The reaction mixture was purified by dialysis
against water, and dried under reduced pressure to provide about
1.13 g (yield, 90%) of the polymer. The molecular weight (Mn=5500)
of the ultimately obtained polymer well coincided with the
theoretical value, and the molecular weight distribution
(Mw/Mn=1.04) was confirmed to be very narrow, on the GPC diagram
(FIG. 7). For structural analysis of the polymer, .sup.1H-NMR
spectrum was used (FIG. 8). Also by the terminal analysis using
MALDI-TOF-MS spectrum, it could be confirmed that both propargyl
group at the initiating terminal and the hydroxyl group at the
termination terminal were quantitatively introduced (FIG. 9).
Test Example 1
Measurement of % transmittance accompanying turbidity change and
determination of cloud point (Cloud Point Temperature; Tcp) of the
polymers therefrom
Using the polymers produced in Production Examples 1-3 (the present
invention), cloud points of the polymers in water due to
temperature change were measured and evaluated. Cloud points of the
homopolymer of iPrOx (PiPrOx.sub.100%) and of the three kinds of
the random copolymers (PEtOx.sub.25%iPrOx.sub.75%,
PEtOx.sub.50%iPrOx.sub.50%, and PEtOx.sub.75%iPrOx.sub.25%) as
synthesized were measured respectively [FIGS. 6-(A), (B)]. In
consequence, it could be confirmed that accurate control of cloud
point of temperature-responsive PiPrOx accompanying the variation
in the blend ratio between iPrOx and EtOx was accomplished over a
wide temperature range (from about 37.degree. C. to 67.degree.
C.).
INDUSTRIAL APPLICABILITY
According to the invention, polymers whose
temperature-responsiveness is controlled so as to show distinct
cloud point or lower critical solution temperature (LCST) at a
certain temperature within a broad range can be provided, which can
be used by industries making or using useful materials in the art
of surface chemistry and biomaterials.
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